As a pediatric infectious disease fellow, I have been impressed with problems due to chronic virus infections in immune-compromised children. My long-range goal is to understand host and viral factors responsible for viral persistence. Human polyomaviruses, JCV and BKV, are nephrotropic viruses acquired early in life that persist asymptommatically in immune competent hosts. SV40 is a polyomavirus of macaque origin that was introduced into the human population as a contaminant of early polio vaccines and has been linked to several human cancers. Recent studies from our laboratory have found an association between SV40 and renal disease in children, especially post-transplant. Based on human and animal studies, others have linked SV40 to focal segmental glomerulosclerosis (FSGS), an enigmatic kidney disease that is increasing in incidence in both children and adults. Children with FSGS are a subset of children with nephrotic syndrome (NS) who fail to respond to steroid therapy and generally progress to end-stage renal disease, necessitating kidney transplantation; FSGS frequently recurs in the new kidney. Our working hypothesis is that SV40 and/or the immune response to SV40 play a role in the pathogenesis of NS and FSGS in children. The experimental approach will also reveal if JCV or BKV play a role in these diseases. Prospective studies of children with NS and various forms of immune suppression will test this hypothesis. Polyomavirus (SV40, JCV and BKV) infection and excretion in these groups and in children from the general pediatric population will be evaluated by PCR and sequence analysis, culminating with an analysis of strain variation to determine whether some viral strains may be more pathogenic than others. Cell-mediated immune responses are vital to the ability of the host to control polyomaviruses. To test the hypothesis that an unbalanced SV40 immune response plays a role in renal disease, SV40-specific antibody titers will be determined by plaque neutralization and SV40-specific cellular immune responses in children will be characterized using a conventional assay of interferon production and, when possible, an HLA-peptide tetramer assay that can identify SV40-specific cytotoxic T lymphocytes. These studies will have implications for the treatment and prevention not only of renal diseases but also for SV40-related malignancies and polyomavirus-related diseases in post-transplant patients and individuals with HIV and AIDS. They also will provide me a firm foundation on which to build an academic career. Dr. Butel's laboratory provides an excellent environment in which to develop my scientific skills.